Improving phase 2/3 trials with an enhanced 2-in-1 adaptive design.

In recent drug development, Phases 2 and 3 are increasingly combined into a seamless Phase 2/3 design to accelerate the drug development process. One of the seamless designs, known as the 2-in-1 adaptive design, allows a Phase 2 trial to expand seamlessly into a Phase 3 study based on an early adaptation decision using surrogate endpoints like ORR (objective response rate) or PFS (progression-free survival). We enhanced this design by incorporating a group sequential approach in the Phase 3 part and adding an interim analysis in the Phase 2 part based on the primary endpoint. This enables re-expansion to Phase 3 and improves the overall probability of success. This enhanced design was applied to an oncology trial to address competitive challenges. In this paper, we prove that the enhanced 2-in-1 design controls the Type I error rate and evaluate its operating characteristics through simulation. Simulation results demonstrate that the correlation between the surrogate endpoint used for early adaptive decisions and the primary endpoint does not impact the overall probability of success. Compared to the original 2-in-1 design, this design increases the probability of success without extending the study duration under the null scenario.